Neuropathic pain is a neurological disorder affecting between 3-8% of the world's population, having unpleasant consequences on patient's quality of life, general mood and occupational functioning [1]. At present, many patients are still considered resistant to current therapy, and thus there is a substantial need for further development of novel medications for the treatment of neuropathic pain [1]. Among the pharmacotherapy used to treat neuropathic pain conditions are antiepileptic drugs (AEDs), e.g. carbamazepine, gabapentin and pregabalin, considered to be among the first line of treatment for several neuropathic pain conditions. It is assumed that both epilepsy and neuropathic pain share underlying common pathophysiology, enabling some AEDs effective in the treatment of several neuropathic pain conditions.
Valproic acid (VPA, 1, FIG. 1) is a broad spectrum AED widely used today for treating various types of epileptic seizures, bipolar disorder and migraine [2]. It was also shown to be effective for treating some forms of neuropathic pain; however, its efficacy as an anti-neuropathic pain (antiallodynic) drug has not been yet established. VPA's clinical use is limited by two severe and life threatening side effects, teratogenicity and hepatotoxicity [3]. Induced hepatotoxicity by VPA is caused by formation of metabolite(s) possessing a terminal double bond (e.g. 4-ene-VPA), however VPA's teratogenicity is caused by the parent compound [4,5]. As a small branched fatty acid having 8 carbons in its structure and a wide range of CNS activity, VPA is a good target for structure modification and structure activity relationship (SAR) studies.
Many studies have been conducted in an attempt to find a superior compound having both a similar broad spectrum of activity as VPA, and an improved side effect profile. Thus, numerous analogues and derivatives of VPA have been synthesized and their anticonvulsant activity evaluated [6-20]. Studies conducted by some of the inventors of the present application evaluated the antiallodynic activity in animal models for neuropathic pain of the corresponding amide of VPA and its constitutional isomers as well as its cyclopropyl analogues [21-22].
Valpromide (VPD, 2), the corresponding amide of VPA, and the constitutional isomers of VPD: valnoctamide (VCD, 3), diisopropylacetamide (DID, 4) and propylisopropylacetamide (PID, 5), (FIG. 1) have been demonstrated to be 10 times more potent as anticonvulsants, and 4 times more potent as anti-neuropathic pain compounds than VPA. In addition, these compounds are also more potent than their corresponding acids, in both anticonvulsant and antiallodynic animal models [21-22].